Anti-candida activity and computational evaluation of chalcones: DFT analysis, ADMET prediction, molecular docking and molecular dynamics simulations

Candida infections remain a major clinical challenge due to the increasing emergence of antifungal resistance, highlighting the need for new therapeutic agents. In this study, a series of 3’-aminochalcones were synthesized, characterized by spectroscopic methods, and evaluated against five Candida species. Compounds C6, C9, and C10 exhibited the highest antifungal activity, with MIC values of 7.8, 15.6, and 15.6 μg/mL against C. albicans, respectively, while C6 showed the highest potency against C. tropicalis (MIC = 1.9 μg/mL). Structure–activity relationship (SAR) analysis indicated that dichloro and trifluoromethyl substituents enhanced antifungal activity. DFT calculations revealed relatively low HOMO-LUMO energy gaps for the most active compounds, supporting their increased chemical reactivity. ADMET predictions suggested favorable drug-likeness and oral bioavailability profiles for all derivatives, although higher toxicity risks were predicted for the most lipophilic compounds. Inverse docking identified lanosterol 14α-demethylase (ERG11) as a potential molecular target. Molecular docking studies suggest favorable interactions between the active chalcones and key residues within the ERG11 active site. Furthermore, molecular dynamics simulations of the ERG11–C6 complex revealed stable protein–ligand interactions throughout the simulation. Overall, these findings identify 3’-aminochalcones as promising antifungal agents.